US9006171B2 - Angiotensin converting enzyme inhibitory peptide - Google Patents

Angiotensin converting enzyme inhibitory peptide Download PDF

Info

Publication number
US9006171B2
US9006171B2 US13/120,531 US200913120531A US9006171B2 US 9006171 B2 US9006171 B2 US 9006171B2 US 200913120531 A US200913120531 A US 200913120531A US 9006171 B2 US9006171 B2 US 9006171B2
Authority
US
United States
Prior art keywords
pro
peptide
composition
peptides
food
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active, expires
Application number
US13/120,531
Other languages
English (en)
Other versions
US20110171690A1 (en
Inventor
Takeharu Nakahara
Riichiro Uchida
Hitomi Aota
Katsutoshi Sugimoto
Takuya Sato
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Kikkoman Corp
Original Assignee
Kikkoman Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Kikkoman Corp filed Critical Kikkoman Corp
Assigned to KIKKOMAN CORPORATION reassignment KIKKOMAN CORPORATION ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: AOTA, HITOMI, NAKAHARA, TAKEHARU, SATO, TAKUYA, SUGIMOTO, KATSUTOSHI, UCHIDA, RIICHIRO
Publication of US20110171690A1 publication Critical patent/US20110171690A1/en
Application granted granted Critical
Publication of US9006171B2 publication Critical patent/US9006171B2/en
Active legal-status Critical Current
Adjusted expiration legal-status Critical

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2/00—Peptides of undefined number of amino acids; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/06—Tripeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06078—Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06104—Dipeptides with the first amino acid being acidic
    • C07K5/06113—Asp- or Asn-amino acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06139—Dipeptides with the first amino acid being heterocyclic
    • C07K5/06165—Dipeptides with the first amino acid being heterocyclic and Pro-amino acid; Derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06139—Dipeptides with the first amino acid being heterocyclic
    • C07K5/06173—Dipeptides with the first amino acid being heterocyclic and Glp-amino acid; Derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
    • C07K5/0806—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
    • C07K5/0808—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0819—Tripeptides with the first amino acid being acidic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to peptides which exert a function of reducing blood pressure by inhibiting angiotensin converting enzyme, compositions comprising these peptides and production methods thereof.
  • Angiotensin converting enzyme (to be referred to as ACE hereinafter) is a kind of carboxypeptidase exists in the animal body and produces angiotensin II by digesting one of the peptide bonds of angiotensin I.
  • the angiotensin II is a peptide hormone having a strong vasopressor activity and causes hypertension through vasoconstriction, acceleration of aldosterone secretion and the like. Accordingly, inhibition of the ACE activity makes control of angiotensin II production and treatment of hypertension possible.
  • medicaments such as captopril and the like have been put into practical use and broadly used as ACE inhibitors. However, since these medicaments have strong actions, there is a possibility of causing side effects and it is necessary to pay attention to side effects such as dry cough and the like in the case of many ACE inhibitors.
  • angiotensin I as the substrate of ACE is a peptide
  • studies have been carried out on the provision of a hypertension treating agent which competitively inhibits ACE by peptides derived from a natural source and shows no side effects (e.g., see Patent References 1 to 5). Since these peptides have mild actions, high safety is expected.
  • a peptide or a composition containing the peptide must be ingested in a relatively large amount in order to ingest its effective amount.
  • a problem to be solved by the present invention is to provide ACE inhibitory peptides which effectively inhibit ACE by a small amount of ingestion; have no fear of causing side effects; and show less bitterness and which can be orally ingested easily during daily life by persons having high blood pressure, compositions comprising the peptides and production methods thereof.
  • the inventors of the present invention have conducted intensive studies and found as a result peptides which have chemical structures (amino acid sequences) in which the presence of an ACE inhibitory action has not so far been known and have markedly strong action to accomplish the present invention.
  • An angiotensin converting enzyme inhibitor which comprises at least one of the peptides described in the above [ 1 ];
  • composition which comprises at least one of the peptides described in the above [1] and alleviates symptoms of high blood pressure;
  • a method for producing the peptides described in the above [1], wherein soybean is mixed and stirred at 25° C. or more with a koji fungus culture are provided.
  • ACE inhibitory peptides which effectively inhibit ACE by a small amount of ingestion; have no fear of causing side effects; and show less bitterness and which can be orally ingested easily during daily life by persons having high blood pressure, compositions comprising these peptides and production methods thereof are provided.
  • FIG. 1 is a figure showing a UV peak when Asp-Arg-Pro was isolated from a composition 1.
  • FIG. 2 is a figure showing changes in the blood pressure value when the composition 1 was administered to high blood pressure rats for a prolonged period of time.
  • the peptides of the present invention (1) Asp-Arg-Pro, (2) Asn-Trp, (3) Val-Gly-Leu, (4) Ile-Gly-Val, (5) Gly-Val-Pro, (6) Ile-Pro-Tyr, (7) pyroGlu-Pro, (8) Tyr-Thr and (9) Pro-Trp are dipeptides or tripeptides in which each amino acid residue was expressed by the generally used three letter code and pyroGlu represents pyroglutamic acid residue. These peptides can be produced, for example, by a chemically synthesizing method.
  • liquid phase method in which amino group of the amino terminus side amino acid is protected with a benzyloxycarbonyl group and the carboxyl group is activated with a p-nitrophenyl ester group and condensed with the carboxyl terminus side amino acid in the presence of triethylamine followed by removal of the protecting group by catalytic reduction or with trifluoroacetic acid and a solid phase method in which the carboxyl terminus side amino acid is bound to a polymeric solid phase support and amino acids after carrying out protection of amino group and activation of carboxyl group are bound thereto one by one by peptide binding followed by removal of the amino acid side chain protecting group by cutting out from the solid phase support using trifluoroacetic acid, hydrogen fluoride or the like.
  • the production can be effected by both of the methods. In this connection, similar effects can be expected from not only a peptide simple substance but also its salt with a physiologically acceptable ion.
  • the peptides of the present invention can also be produced using a column chromatography or the like, by separation and purification from a composition prepared by hydrolyzing a protein containing said amino acid sequence with an appropriate protease agent.
  • the intended effect can be obtained even when ingested in the form of a composition containing said peptide. This is more desirable because mass production is easy and production cost is low, in comparison with the aforementioned chemical synthesis methods.
  • the protein source in the case of obtaining the peptide of the present invention by hydrolysis of protein although any material may be used as long as the object of the present invention can be achieved, preferably, it is suitable to use a leguminous plant. More preferably, it is desirable to use soybean from the viewpoints that its cultivation quantity is large; its cost is low; its protein content is large; its eating experience is rich; and taste of the composition after hydrolysis is good.
  • the kind of soybean includes a yellow soybean, a red soybean, a black soybean and the like and a yellow soybean is particularly desirable.
  • whole soybean whole soybean
  • defatted soybean, purified soybean protein and the like can be used as such or by applying an optional protein denaturation treatment after crushing and pulverization.
  • the protein denaturation treatment the industrially broadly used pressure cooking is preferable.
  • the protease agent in the case of obtaining the peptide of the present invention by hydrolysis of protein although any material may be used as long as the object of the invention can be achieved, it is suitable to use a koji fungus culture from the viewpoints that its protease activity is high; its cost is low; its eating experience is rich; its safety is guaranteed; and taste of the composition after hydrolysis is good.
  • Aspergillus oryzae and/or Aspergillus sojae is particularly suitable.
  • the koji fungus culture is a product obtained by inoculating and culturing a koji fungus using soybean, wheat, rice etc. as the medium. It is classified into a liquid koji culture and a solid koji culture based on the difference in culturing method and both cases can be used in the present invention.
  • a liquid koji culture can be obtained by inoculating a koji fungus into a liquid medium containing from 1% to 5% of soybean, wheat, wheat bran and the like and culturing it at from 25° C. to 40° C. for from 24 hours to 120 hours.
  • a solid koji culture mixture can be obtained by inoculating a koji fungus on a solid medium containing soybean, wheat and the like and culturing it at from 25° C. to 40° C. for from 24 hours to 120 hours.
  • from 10% to 70%, preferably from 30% to 50%, in final concentration of a koji fungus culture is mixed with from 5% to 40%, preferably from 15% to 30%, in final concentration of soybean; from 0% to 25%, preferably from 6% to 18%, in final concentration of salt; and further from 0% to 85% in final concentration of water, and final concentrations of soybean and salt are adjusted to the aforementioned ranges, followed by the reaction at from 25° C. to 60° C., preferably from 30° C. to 55° C., at an agitation rate of from 10 rpm to 150 rpm for from 12 hours to 240 hours, preferably from 24 hours to 168 hours.
  • a yeast strain belonging to the genus Zygosaccharomyces or the like are simultaneously carry out the fermentation.
  • the composition prepared by the aforementioned production method can be deliciously ingested as food because bitterness can hardly be felt and it has mellow and rich deliciousness and body and mild and superior aroma, which is and markedly different form the conventionally known ACE inhibitory peptide-containing compositions.
  • the methods for separating and purifying the peptide of the present invention from the aforementioned composition include ultrafiltration, dialysis, various types of chromatography and the like can be mentioned. These are generally broadly used methods. Particularly, a cation exchange chromatography and a reverse phase chromatography are effective from the viewpoint of treating amount of samples and purification efficiency.
  • the peptide of the present invention obtained in this manner can be used by oral or parenteral administration as an ACE inhibitor, namely a blood pressure increase inhibiting/reducing agent.
  • an ACE inhibitor namely a blood pressure increase inhibiting/reducing agent.
  • it can be made into forms such as tablets, granules, powders, capsules and the like in the case of the oral administration, and can be made into forms such as injection preparations, percutaneous preparations, suppositories and the like in the case of parenteral administration.
  • the peptide of the present invention can be produced by adding it to various types of food and drink, and since its taste is good even in the form of a peptide-containing composition as described above, its addition to various types of food and drink is easy. Furthermore, it is also easy to ingest the composition itself.
  • Examples of the food and drink obtained in this manner include soy sauce, soy sauce containing product, powder soy sauce, soybean paste, tsuyu and soups, broths, soybean milk, fermented milk, soft drink, concentrated drink stock liquid and adjusting powder, liquors, oil and fat-containing food, noodles, processed seafood, processed meat food, semi-solid food, pasty food, solid food and the like.
  • IC 50 the ACE inhibitory activity represented by IC 50 becomes 1 mg/ml or less as a whole.
  • Asn-Trp Production of Asn-Trp is exemplified in the following.
  • the reagents other than the particularly mentioned ones those produced by Wako Pure Chemical Industries, Ltd. were used. Firstly, 120 mg of L-tryptophan hydrochloride was dissolved in 2 ml of dimethylformamide, and 150 ⁇ l of triethylamine and 300 mg of Z-Asn-Onp (manufactured by KOKUSAN CHEMICAL Co., Ltd.) were added and stirred at room temperature for 24 hours. Next, 20 ml of 1% aqueous ammonia was added and allowed to stand at ⁇ 10° C. for 1 hour. The formed precipitate was collected by filtration and the precipitate was washed with cold water.
  • the precipitate was dissolved in 20 ml of methanol; 20 mg of palladium activated carbon was added thereto; and, after nitrogen gas sealing, a catalytic reduction reaction was carried out.
  • the reaction was carried out at room temperature for 3 days by contacting with hydrogen gas while with under atmospheric pressure. After the reaction, the insoluble matter was removed by filtration and methanol was evaporated, followed by dissolution in distilled water. Next, fractionation purification was carried out by an ODS column (Cosmosil 5C18-ARII 20 ⁇ 250 mm, manufactured by Nakalai Tesque) connected to an HPLC (LC-8A, manufactured by Shimadzu Corp.).
  • ACE inhibitory activity of the peptides obtained by the aforementioned synthesis method was measured.
  • the measuring method it was carried out by a method in which the method of Yamamoto et al. (Setsuko Yamamoto et al., Journal of the Japan Society of Chest Diseases, 1980, 18, p. 297-302) was partially modified.
  • sample solution 140 ⁇ l of sample solution, 10 ⁇ l of enzyme solution (0.3 U/ml of ACE (rabbit lung-derived, manufactured by SIGMA) and 50 mM borate buffer (pH 8.3) were added to 100 ⁇ l of a substrate solution (12.5 mM Hippuryl-His-Leu (manufactured by SIGMA), 100 mM borate buffer pH 8.3, 1M NaCl), and the reaction was carried out at 37° C. for 30 minutes.
  • enzyme solution 0.3 U/ml of ACE (rabbit lung-derived, manufactured by SIGMA)
  • borate buffer pH 8.3
  • ODs is the absorbance when the reaction was carried out by adding the enzyme solution to a sample as described above; ODsb is the absorbance when ultrapure water was added instead of the enzyme solution; ODc is the absorbance when ultrapure water was added instead of the sample solution; and ODcb is the absorbance when ultrapure water was added instead of the enzyme solution and sample solution.
  • concentration of a sample which gives 50% of the enzyme activity inhibitory ratio on this reaction system is regarded as the IC 50 value.
  • ACE inhibitory activities of the peptides of the present invention are shown in Table 1.
  • the IC 50 value of about 400 species of the main ACE inhibitory peptides so far reported was approximately from 1 ⁇ M to 1000 ⁇ M (“Shoku no Kagaku Library 3 Shokuhin Seibun no Hataraki (Science Library of Food 3 Action of Food Components)”, edited by Koji Yamada, Asakura Shoten, March, 2004, p. 63-67). Since the peptides of the present invention have sufficiently strong activities in comparison with the conventionally known peptides, it is considered that they are industrially useful.
  • composition 1 the insoluble solid matter was removed from the moromi using a hydraulic filter press to obtain a supernatant.
  • enzyme deactivation and sterilization through heating at 117° C. for 5 seconds using an HS sterilizer (manufactured by HISAKA WORKS, LTD.) followed by standing still at 50° C. for 3 days, 20 liters of a supernatant alone containing no sediment was collected (composition 1).
  • the above-mentioned freeze-dried powder was dissolved in ultrapure water and then loaded on an ODS column (Cosmosil 5C18-ARII 20 ⁇ 250 mm, manufactured by Nakalai Tesque) connected to a high performance liquid chromatography (HPLC, manufactured by Shimadzu Corporation).
  • ODS column Cosmosil 5C18-ARII 20 ⁇ 250 mm, manufactured by Nakalai Tesque
  • HPLC high performance liquid chromatography
  • each fraction having the ACE inhibitory activity was loaded on a C30 column (Develosil RPAQUEOUS-AR 20 ⁇ 250 mm, manufactured by NOMURA CHEMICAL CO., LTD.).
  • a C30 column Develosil RPAQUEOUS-AR 20 ⁇ 250 mm, manufactured by NOMURA CHEMICAL CO., LTD.
  • acetonitrile+0.1% TFA as the eluent B
  • fractionation was carried out with a fraction size of 6 ml, at a flow rate of 5 ml/min under gradient conditions of (A 100%: 10 minutes) ⁇ (gradient until B 30%: 60 minutes) ⁇ (gradient until B 100%: 30 minutes). Its chromatogram is shown in FIG. 1 .
  • the ACE inhibitory activity was measured, the activity was found only on the peak shown by arrow.
  • the peptides of the present invention contained in the composition 1 were determined. Firstly, a calibration curve was prepared using a peptide obtained by a chemical synthesis as the standard. Next, the composition 1 was desalted by electrodialysis and optionally diluted to carry out its analysis to calculate the content from the detected amount of ion derived from each peptide. The results are shown in Table 2.
  • compositions obtained by production methods having different conditions are shown in Table 3.
  • wheat was used instead of soybean, and a protease agent for food use (Alcalase 2.4L-FG, manufactured by NOVOZYMES) instead of the koji fungus culture.
  • Alcalase 2.4L-FG manufactured by NOVOZYMES
  • koji fungus culture is superior as the enzyme preparation
  • 25° C. or more is superior as the reaction temperature.
  • the peptides of the present invention can be produced particularly efficiently, by mixing and stirring soybean at 25° C. or more with the koji fungus culture.
  • control ( ⁇ in the drawing): a feed prepared by mixing 25% v/w of a low salt soy sauce (salt concentration 7% w/v) based on the feed (salt concentration in the feed: 3% w/w).
  • composition 1 ( ⁇ in the drawing): a feed prepared by mixing 20% v/v of the aforementioned composition 1 with the low salt soy sauce and mixing 25% v/w thereof based on the feed (salt concentration in the feed: 3% w/w and composition 1 concentration: 1.5% w/w).
  • Third group (a fraction obtained by removing peptides from the composition 1) ( ⁇ in the drawing): a feed prepared by mixing the aforementioned ODS-A fraction (a fraction hardly containing peptides, prepared by fractionating the composition 1 by an ODS column) with the low salt soy sauce and mixing 25% v/w thereof based on the feed (salt concentration in the feed: 3% w/w and ODS-A fraction concentration: 1.3% w/w).
  • composition 1 containing the peptides of the present invention significantly inhibited increase of blood pressure. Additionally, while hypotensive action was found in the peptide-containing fractions, the hypotensive action was lost by the degradation of peptides. Therefore, it was shown that the hypotensive action of composition 1 is derived from peptides.
  • the sensory evaluation was carried out using the composition 1 and Comparative Example 1 described in Example 2.
  • “strength of bitterness” and “desirableness of taste” were evaluated by a paired comparison method. From the results of Table 4, it can be understood that although the fermented seasoning of the present invention is rich in peptides, it shows less bitterness and has a suitable taste. Although a large number of peptide production methods which use protease agents have so far been disclosed, it is considered that the present invention is superior to the related art in terms of its taste.
  • the angiotensin converting enzyme inhibitory peptides obtained by the present invention effectively inhibit ACE by a small amount of ingestion and have no fear of causing side effects and can be orally ingested easily during daily life by persons having high blood pressure. Additionally, by the presentation of the production methods of compositions which contain said peptides; are excellent in taste; have high safety; and can be easily ingested as food, it becomes possible to greatly contribute to the improvement of quality of life of persons having high blood pressure.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Molecular Biology (AREA)
  • Genetics & Genomics (AREA)
  • Biophysics (AREA)
  • Biochemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Immunology (AREA)
  • Epidemiology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Coloring Foods And Improving Nutritive Qualities (AREA)
US13/120,531 2009-01-19 2009-02-06 Angiotensin converting enzyme inhibitory peptide Active 2030-01-24 US9006171B2 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
JP2009-008503 2009-01-19
JP2009008503A JP2010163400A (ja) 2009-01-19 2009-01-19 新規アンジオテンシン変換酵素阻害ペプチド
PCT/JP2009/052108 WO2010082367A1 (ja) 2009-01-19 2009-02-06 アンジオテンシン変換酵素阻害ペプチド

Publications (2)

Publication Number Publication Date
US20110171690A1 US20110171690A1 (en) 2011-07-14
US9006171B2 true US9006171B2 (en) 2015-04-14

Family

ID=42339632

Family Applications (2)

Application Number Title Priority Date Filing Date
US13/120,531 Active 2030-01-24 US9006171B2 (en) 2009-01-19 2009-02-06 Angiotensin converting enzyme inhibitory peptide
US14/014,559 Abandoned US20130345396A1 (en) 2009-01-19 2013-08-30 Angiotensin converting enzyme inhibitory peptide

Family Applications After (1)

Application Number Title Priority Date Filing Date
US14/014,559 Abandoned US20130345396A1 (en) 2009-01-19 2013-08-30 Angiotensin converting enzyme inhibitory peptide

Country Status (6)

Country Link
US (2) US9006171B2 (de)
EP (1) EP2380901B1 (de)
JP (1) JP2010163400A (de)
KR (1) KR101653012B1 (de)
CN (1) CN102164946B (de)
WO (1) WO2010082367A1 (de)

Families Citing this family (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP5729297B2 (ja) * 2009-07-13 2015-06-03 不二製油株式会社 経口性抗炎症剤及び経口性抗炎症ペプチド
CN102304169B (zh) * 2011-08-05 2013-03-20 成都中医药大学 降血压多肽及其用途
JP5456144B1 (ja) * 2012-11-21 2014-03-26 ヤマキ株式会社 アンジオテンシン変換酵素阻害ジペプチド
US20150183822A1 (en) * 2012-06-26 2015-07-02 Yamaki Co., Ltd. Angiotensin-converting-enzyme inhibiting dipeptide
CN105002249B (zh) * 2015-08-14 2018-09-21 湖北工业大学 一种红曲霉液态发酵制备ace抑制肽的方法
US10676505B2 (en) 2016-06-16 2020-06-09 Sunstar Inc. Tripeptides having angiotensin converting enzyme inhibitory activity and uses thereof
CN106755244A (zh) * 2016-12-29 2017-05-31 陕西科技大学 一种风味蛋白酶酶解制备ace抑制肽的方法
CN106755242A (zh) * 2016-12-29 2017-05-31 陕西科技大学 一种魔芋蛋白ace抑制肽的制备方法
WO2019006951A1 (zh) * 2017-07-07 2019-01-10 广州世优生物科技有限公司 非极性二肽在制备降血压药物或保健品中的应用
CN110317824B (zh) * 2018-03-29 2021-03-05 中国科学院植物研究所 降血压水稻材料的制备方法及所用基因与蛋白质
KR102209870B1 (ko) * 2019-03-13 2021-02-03 강원대학교산학협력단 항고혈압 활성 펩타이드, 그의 제조방법 및 그의 용도
CN110467649A (zh) * 2019-09-12 2019-11-19 浙江省农业科学院 一种抑制血管紧张素转换酶活性的多肽qeip及其应用

Citations (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0491097A (ja) 1990-08-03 1992-03-24 Nisshin Flour Milling Co Ltd 新規なペプチド及びアンジオテンシン変換酵素阻害剤
JPH05262790A (ja) 1991-06-03 1993-10-12 Takara Shuzo Co Ltd 新規ペプチド
JPH05339166A (ja) 1992-06-03 1993-12-21 Abo Sadakichi アンジオテンシン変換酵素阻害物質およびその製造法
JPH0640944A (ja) 1992-07-23 1994-02-15 Calpis Food Ind Co Ltd:The アンジオテンシン変換酵素阻害剤及びその製造法
JPH07188282A (ja) 1991-04-19 1995-07-25 Suetsuna Yoko 新規なトリペプチド、その製法およびそれを有効成分と する血圧降下剤
JPH08269087A (ja) 1992-03-02 1996-10-15 Fumio Yamauchi 新規なテトラペプチド、ペンタペプチドその製法およびそれらを有効成分とする血圧降下剤
JPH10175997A (ja) 1996-12-12 1998-06-30 Shirako:Kk 海苔から得られるペプチド混合物
JP2002053595A (ja) 2000-08-14 2002-02-19 Abo Kenji アンジオテンシン変換酵素阻害物質とその製造法
WO2002055546A1 (fr) 2001-01-16 2002-07-18 Ajinomoto Co.,Inc. Inhibiteurs de l'enzyme de conversion de l'angiotensine
WO2004082709A1 (en) 2003-03-18 2004-09-30 Suntory Limited Angiotensin-converting enzyme inhibitory peptides
CN1731934A (zh) 2002-12-24 2006-02-08 加拿大农业及农业食品部 源自植物材料的ace抑制肽
JP2006075064A (ja) 2004-09-09 2006-03-23 Sanei Gen Ffi Inc ペプチド含有飲料
JP2007008846A (ja) 2005-06-29 2007-01-18 Kikkoman Corp 血管内皮機能改善組成物
JP2008088151A (ja) 2006-09-08 2008-04-17 Higashimaru Shoyu Co Ltd 醤油に含まれる高分子物質の用途
JP2009040696A (ja) 2007-08-07 2009-02-26 Kikkoman Corp 新規アンジオテンシン変換酵素阻害ペプチド

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH07188283A (ja) * 1991-04-19 1995-07-25 Suetsuna Yoko 新規なトリペプチドおよびアンジオテンシン変換酵素 阻害剤
JP3083245B2 (ja) 1995-06-22 2000-09-04 喜弘 井上 積重容器の除塵装置
US9274101B2 (en) * 2001-04-20 2016-03-01 Biolog, Inc. Methods and kits for obtaining a metabolic profile of living animal cells
JP2007008876A (ja) * 2005-06-30 2007-01-18 Avant Immunotherapeutics Inc 脊髄損傷を治療するための補体阻害タンパク質の使用
JP4926854B2 (ja) 2007-06-27 2012-05-09 シスメックス株式会社 血小板凝集測定方法および血小板凝集測定装置

Patent Citations (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0491097A (ja) 1990-08-03 1992-03-24 Nisshin Flour Milling Co Ltd 新規なペプチド及びアンジオテンシン変換酵素阻害剤
JPH07188282A (ja) 1991-04-19 1995-07-25 Suetsuna Yoko 新規なトリペプチド、その製法およびそれを有効成分と する血圧降下剤
JPH05262790A (ja) 1991-06-03 1993-10-12 Takara Shuzo Co Ltd 新規ペプチド
JPH08269087A (ja) 1992-03-02 1996-10-15 Fumio Yamauchi 新規なテトラペプチド、ペンタペプチドその製法およびそれらを有効成分とする血圧降下剤
JPH05339166A (ja) 1992-06-03 1993-12-21 Abo Sadakichi アンジオテンシン変換酵素阻害物質およびその製造法
JPH0640944A (ja) 1992-07-23 1994-02-15 Calpis Food Ind Co Ltd:The アンジオテンシン変換酵素阻害剤及びその製造法
JPH10175997A (ja) 1996-12-12 1998-06-30 Shirako:Kk 海苔から得られるペプチド混合物
JP2002053595A (ja) 2000-08-14 2002-02-19 Abo Kenji アンジオテンシン変換酵素阻害物質とその製造法
WO2002055546A1 (fr) 2001-01-16 2002-07-18 Ajinomoto Co.,Inc. Inhibiteurs de l'enzyme de conversion de l'angiotensine
US20040014670A1 (en) 2001-01-16 2004-01-22 Ajinomoto Co. Inc Inhibitors of angiotensin converting enzyme
CN1731934A (zh) 2002-12-24 2006-02-08 加拿大农业及农业食品部 源自植物材料的ace抑制肽
US20060217318A1 (en) 2002-12-24 2006-09-28 Jian-Ping Wu Ace inhibitory peptides from plant materials
WO2004082709A1 (en) 2003-03-18 2004-09-30 Suntory Limited Angiotensin-converting enzyme inhibitory peptides
JP2006075064A (ja) 2004-09-09 2006-03-23 Sanei Gen Ffi Inc ペプチド含有飲料
JP2007008846A (ja) 2005-06-29 2007-01-18 Kikkoman Corp 血管内皮機能改善組成物
JP2008088151A (ja) 2006-09-08 2008-04-17 Higashimaru Shoyu Co Ltd 醤油に含まれる高分子物質の用途
JP2009040696A (ja) 2007-08-07 2009-02-26 Kikkoman Corp 新規アンジオテンシン変換酵素阻害ペプチド

Non-Patent Citations (15)

* Cited by examiner, † Cited by third party
Title
Auna et al., "Results of a study of myotropic action of common fragments of some peptide hormones," Latvijas PSR Zinatnu Akademijas Vestis 7:104-9 (1975)-in Russian. *
Auna et al., "Results of a study of myotropic action of common fragments of some peptide hormones," Latvijas PSR Zinatnu Akademijas Vestis 7:104-9 (1975)—in Russian. *
Chinese Office Action dated Oct. 21, 2013, issued in corresponding Chinese Patent Application No. 200980137462.5, and English translation.
Database BIOSIS [Online], Biosciences Information Service, 1975, Auna, Z.P. et al., Results of a study of myotropic action of common fragments of some peptide hormones, XP00268916, Database accession No. PREV197661054425.
Database STN Chemical Abstracts [Online], Vegners, R. et al., Synthesis and study of the biological activity of some arginine- and lysine-containing fragments of peptide hormones, XP002055234, retrieved from Chemical Database accession No. 60189, published 1973.
International Search Report for PCT/JP2009/052108 dated Apr. 28, 2009.
Japanese Appl. No. JP 2007-008846 A, published Jan. 18, 2007, machine translation from the Japanese patent office, accessed Jul. 16, 2013, pp. 1-9. *
Japanese Office Action dated Aug. 22, 2013, issued in corresponding Japanese Patent Application No. 2009-008503, and English translation.
Kaitei Shinpan Shokuhin Kagaku (Revised New Edition Food Chemistry), Masao Fujimaki ed., Asakura Shoten, Mar. 1976, p. 117-118.
PTO 13-5153, English translation of Vegner et al.,Vegners et al., "Synthesis and study of the biological activity of some arginine- and lysine-containing fragments of peptide hormones," Khim. Prir. Soedin. 9:516-24 (1973). *
PTO 13-5158, English translation of Auna et al., "Results of a study of myotropic action of common fragments of some peptide hormones," Latvijas PSR Zinatnu Akademijas Vestis 7:104-9 (1975). *
Supplementary European Search Report dated Nov. 22, 2012, issued in corresponding European Application No. 09838334.2.
Vegners et al., "Synthesis and study of the biological activity of some arginine- and lysine-containing fragments of peptide hormones," Khim. Prir. Soedin. 9:516-24 (1973)-in Russian. *
Vegners et al., "Synthesis and study of the biological activity of some arginine- and lysine-containing fragments of peptide hormones," Khim. Prir. Soedin. 9:516-24 (1973)—in Russian. *
Wang, Wenyi et al., A New Frontier in Soy Bioactive Peptides that May Prevent Age-related Chronic Diseases, Comprehensive Reviews in Food Science and Food Safety, 4:63-78 (2005).

Also Published As

Publication number Publication date
EP2380901A4 (de) 2012-12-26
US20130345396A1 (en) 2013-12-26
EP2380901A1 (de) 2011-10-26
EP2380901B1 (de) 2019-07-17
KR101653012B1 (ko) 2016-08-31
WO2010082367A1 (ja) 2010-07-22
CN102164946B (zh) 2016-02-17
JP2010163400A (ja) 2010-07-29
US20110171690A1 (en) 2011-07-14
CN102164946A (zh) 2011-08-24
KR20110105761A (ko) 2011-09-27

Similar Documents

Publication Publication Date Title
US9006171B2 (en) Angiotensin converting enzyme inhibitory peptide
Aluko Antihypertensive peptides from food proteins
Enari et al. Identification of angiotensin I-converting enzyme inhibitory peptides derived from salmon muscle and their antihypertensive effect
Mallikarjun Gouda et al. Angiotensin I-converting enzyme inhibitory peptide derived from glycinin, the 11S globulin of soybean (Glycine max)
Byun et al. Structure and activity of angiotensin I converting enzyme inhibitory peptides derived from Alaskan pollack skin
Lee et al. Isolation and characterization of a novel angiotensin I-converting enzyme inhibitory peptide derived from the edible mushroom Tricholoma giganteum
EP1605969B1 (de) Das angiotensin-conversions-enzym hemmende peptide
US9617300B2 (en) Dipeptidyl peptidase-IV inhibitor
AU2002366037B2 (en) Novel peptide having angiotensin convertase inhibitory effect
JP5417405B2 (ja) アンジオテンシン変換酵素阻害性降圧ペプチド組成物の製造方法
JP5416964B2 (ja) 新規トリペプチドおよびそれらトリペプチドの製造法、ならびにアンジオテンシン変換酵素阻害物質の製造方法
WO2014002571A1 (ja) アンジオテンシン変換酵素阻害ジペプチド
WO2005061529A1 (ja) アンジオテンシン変換酵素阻害ペプチド
WO2013133032A1 (ja) ジペプチジルペプチダーゼ－ｉｖ阻害剤
JP5456100B2 (ja) アンジオテンシン変換酵素阻害ジペプチド
CA2642539C (en) Agent for preventing arteriosclerosis, agent for suppressing vascular intimal thickening and agent for improving vascular endothelial function
JP5456144B1 (ja) アンジオテンシン変換酵素阻害ジペプチド
JP2009040696A (ja) 新規アンジオテンシン変換酵素阻害ペプチド
JP4934369B2 (ja) 血圧低下作用を有するペプチド
JP2014138617A (ja) アンジオテンシン変換酵素阻害ペプチド含有組成物
JP2013241470A (ja) ペプチド含有組成物
JP2003024012A (ja) アンジオテンシンｉ変換酵素阻害剤及び血圧降下性機能食品
JP2000191690A (ja) アンジオテンシン変換酵素阻害性ペプチド

Legal Events

Date Code Title Description
AS Assignment

Owner name: KIKKOMAN CORPORATION, JAPAN

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:NAKAHARA, TAKEHARU;UCHIDA, RIICHIRO;AOTA, HITOMI;AND OTHERS;REEL/FRAME:026005/0921

Effective date: 20110225

FEPP Fee payment procedure

Free format text: PAYOR NUMBER ASSIGNED (ORIGINAL EVENT CODE: ASPN); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY

STCF Information on status: patent grant

Free format text: PATENTED CASE

MAFP Maintenance fee payment

Free format text: PAYMENT OF MAINTENANCE FEE, 4TH YEAR, LARGE ENTITY (ORIGINAL EVENT CODE: M1551); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY

Year of fee payment: 4

MAFP Maintenance fee payment

Free format text: PAYMENT OF MAINTENANCE FEE, 8TH YEAR, LARGE ENTITY (ORIGINAL EVENT CODE: M1552); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY

Year of fee payment: 8